CN105378463B - For detecting the device of binding affinity - Google Patents
For detecting the device of binding affinity Download PDFInfo
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- CN105378463B CN105378463B CN201480039853.4A CN201480039853A CN105378463B CN 105378463 B CN105378463 B CN 105378463B CN 201480039853 A CN201480039853 A CN 201480039853A CN 105378463 B CN105378463 B CN 105378463B
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- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
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Abstract
A kind of device (1) for detecting binding affinity, including the slab guide (2) being arranged on substrate (22).Waveguide (2) has outer surface (21) and for coherent beam to be coupled in waveguide (2), so that multiple input coupling lines (31) that parallel coherent beam (62) is propagated along waveguide (2).Input coupling line (31) is curved and has cumulative distance between adjacent input coupling line (31).The coherent beam (61) of the diverging of predetermined wavelength is coupled in waveguide (2), propagates it along waveguide (2).Multiple binding sites (51) are attached on outer surface (21) along the other multiple diffracted rays at least one of output coupling portion for being arranged in waveguide (2).These diffracted rays include multiple curved output coupling lines (41) between adjacent output coupling line with decrescence distance.These output coupling lines decouple the diffracted portion of coherent light from slab guide (2), and the decoupling Part Convergence of coherent light (63) is to predetermined second focal position (631).
Description
Technical field
The present invention relates to the devices for detecting binding affinity, and are related to the side according to corresponding independent claims
Method.
Background technique
The device is used as such as biosensor in various applications.One special application is that detection or monitoring combine
Affinity or process.For example, being able to carry out the combination of detection target sample to binding site by means of this biosensor
Various measurements.Typically, at the point being arranged on biosensor surface with two-dimentional microarray, on a biosensor into
The a large amount of this measurement of row.The use of microarray provides in high-throughput screening while detecting the combination of different target sample
The tool of affinity or process.In order to detect the affinity that target sample is integrated to specific binding site, for example, target molecule
The affinity of specific capture molecule is integrated to, on the outer surface that a large amount of capture molecule is fixed on biosensor at each
(for example, passing through ink-jet spotting method or photoetching process).Each point forms the single measurement zone of the capture molecule of predefined type
Domain.The combination of target molecule to certain types of capture molecule is detected and is used to provide to catch about target molecule relative to specific
Obtain the information of the binding affinity of molecule.
The technology of the known binding affinity for being used to detect target sample uses fluorescent marker.Fluorescent marker can swash
Emit fluorescence when hair.The fluorescence emitted has the characteristic emission spectrum of current fluorescent marker of the identification at specified point.It is identified
Fluorescent marker instruction, the target molecule of marking is in conjunction with the certain types of binding site being present at the point.
It is a kind of to be described in following paper for detecting the sensor of target sample labelled: " the albumen of Zeptosens
Matter microarray: a kind of novel high-performance microarray platform for low abundance proteins analysis ", Proteomics 2002,2,
S.383-393, Wiley-VCH Verlag GmbH, 69451Weinheim, Germany.Wherein described sensor includes
The slab guide being arranged on substrate.Slab guide has outer surface that can be attached to it by multiple binding sites.Moreover,
Slab guide has multiple for coherent beam to be coupled to slab guide in such a way that coherent beam is propagated along slab guide
In input coupling line (incoupling lines).In the feelings that the evanescent field of coherent light is propagated along the outer surface of slab guide
Under condition, coherent light propagates through slab guide under total reflection.In the lower folding of evanescent field injection of the outer surface of slab guide
The depth penetrated in rate medium is on the order of magnitude of the magnitude of the fraction of the wavelength for the coherent light for propagating through slab guide.Fadout
The fluorescent marker of the target sample of marking in conjunction with the binding site on the surface for being arranged in slab guide is swashed field
Hair.Since the outer surface evanescent field injection in slab guide is optically compared with the minimum depth in thin-medium, only make with
The marking sample that the binding site being fixed on slab guide outer surface combines is excited.Then, come by means of CCD camera
The fluorescence that detection is emitted by these labels.
Although can detect binding affinity using fluorescent marker in principle, which is disadvantageous in that,
The signal of detection be generated by fluorescent marker, rather than by combine pairing person itself generate.In addition, adding to target sample
Label needs additional preparation step.Moreover, the target sample labelled is relatively expensive.Further drawback is, by fluorescent marker
The falsfication of result caused by steric hindrance at the target sample, may interfere with the combination of target sample and capture molecule.In addition
The disadvantage is that, the falsfication of the result as caused by the photobleaching or quenching effect of label.
Summary of the invention
The object of the present invention is to provide the device for detecting the binding affinity between target sample and binding site, with
And it is capable of providing the side of the signal of the binding affinity for the shortcomings that characterization overcomes or the above-mentioned prior art is at least greatly reduced
Method.
According to the present invention, which realized by the device for detecting binding affinity.The device includes cloth
Set the slab guide on substrate.Slab guide has outer surface and multiple input coupling lines, the multiple input coupling line
For being incited somebody to action in such a way that coherent beam parallel in operation is propagated along slab guide propagation and evanescent field along its outer surface
Coherent beam is coupled in slab guide.Multiple input coupling lines are curved and are arranged to, when parallel coherent beam along
When the side that slab guide is propagated looks up, there are cumulative distance, multiple input couplings between adjacent input coupling line
The distance between the arrangement of line and adjacent input coupling line make, and in operation, from scheduled first focal position and hit
Hit the side that the diverging coherent beam of the predetermined wavelength of multiple input coupling lines is propagated with parallel coherent beam along slab guide
Formula is coupled in slab guide.The multiple binding sites for capableing of combining target sample are attached on outer surface.The engaging portion of attachment
Spread out along other multiple at least one of output coupling portion (outcoupling section) for being arranged in slab guide position
Ray arrangement.At least one other multiple diffracted ray includes multiple curved output coupling lines, these curved output couplings
Line is arranged to have between adjacent bending output coupling line when looking up in the side for hitting the relevant light propagation above it
There is distance decrescence, so as to a part of the coherent light of diffraction predetermined wavelength, so that it is with the coherent light of predetermined wavelength
It decouples Part Convergence to decouple to the mode of scheduled second focal position from slab guide, to provide at the second focal position
Characterize the signal of the binding affinity between binding site and target sample.
It is worth noting that, term " curved output coupling line " includes the two, that is, " true " line (real lines),
It is with optical diffraction effect (line being physically present, such as grid stroke) and by a part of diffraction of the coherent light of predetermined wavelength
To scheduled second focal position, (in this case, binding site is along other multiple " virtual " lines (virtual lines)
Arrange and be formed together biological grid with target sample, thus towards a part of the parallel coherent beam of " true " line diffraction),
And " virtual " line (does not exist in physically on the outer surface of waveguide or itself does not have optical diffraction effect but pass through edge
The binding site of these " virtual " lines arrangement formed and be formed together the line of biological grid with target sample).Two kinds " curved
A part of the coherent light of predetermined wavelength is diffracted into scheduled second coke by output coupling line ", " true " line and " virtual " line
Point position.In the latter cases, that is, when curved output coupling line is formed by " virtual " line of biological grid, in addition to biology
Except grid, " true " line of such as those of grating line may exist or can be not present.
Term " curved input coupling line " is also including the two, i.e. " true " line, (physically with optical diffraction effect
Existing line, such as grid stroke) and a part of the coherent light of diffraction predetermined wavelength the diffracted portion of coherent light to be coupled to
In slab guide, and " virtual " line (does not exist in physically on the outer surface of waveguide or itself does not have optical diffraction and imitate
It should still be formed to be formed together biological grid together with target sample by the binding site arranged along these " virtual " lines
Line)." true " line can for example be embodied as curved physical cord, and diverging coherent beam is coupled in waveguide, and " empty
It is quasi- " line can be curved line, the coherent beam of dispersion is coupled in slab guide, binding site is along these dummy lines
Arrangement and diverging of the diffraction (together with target sample in connection) from point light source (being arranged in pre-position) is relevant
A part of light beam and the diffracted portion of coherent light is coupled in slab guide.When in the coherent light being coupled in slab guide
The direction of propagation on when observing, curved input coupling line (" true " line or " virtual " line) has distance cumulative each other.Cause
This is it is possible that input coupling line and output coupling line can all only include biological grid (without " true " line).This is manufacturing this
It is beneficial when a little grids, because the manufacture of both input coupling line and output coupling line is then able to using photoetching technique in list
It is carried out in a step.This can enable the manufacture of grid is more cheap.
In operation, the diffraction in the output coupling portion at the attachment binding site in conjunction with the target sample applied
Coherent light (being formed together biological grid) can be arranged at the second focal position, the measurement as binding affinity.For example, will
Be located at the coherent light at scheduled second focal position intensity carry out detection and with only (do not had by binding site diffraction
The target sample of application) the known strength of coherent light be compared.Intensity variation characterization binding site and target sample it
Between binding affinity (that is, being the measurement of the binding affinity between binding site and target sample), this is because due to mesh
Standard specimen originally in conjunction with binding site, so when and the intensity in only scheduled second focal position caused by binding site
Compared to when, the intensity at scheduled second focal position is dramatically different.Which overcome the needs labelled to target sample, because
Constructively interfere at scheduled second focal position and detectable signal is provided in output coupling part for coherent light."
Constructively interfere at scheduled second focal position " in other words refer to and is converged at scheduled second focal position
Coherent light at scheduled second focal position has optical path length difference, is the integral multiple of predetermined wavelength.Scheduled second
The interference maximum value at focal position provides the detectable signal for the binding site being derived from conjunction with target sample.
Generally, " binding site " is that target sample on the outer surface of slab guide can combine and (or combine parent
Combined in the case where power) position.The detection of binding affinity according to the present invention is neither limited to certain types of target sample
This, and it is not limited to any kind of binding site, but the binding characteristic such as molecule, protein, DNA, because being capable of phase
The binding site of any suitable type in slab guide analyzes target sample.Technically, term " spreads out
Penetrate " indicate the interference with the coherent light of the evanescent field for the target sample interaction for being integrated to binding site.Term diffraction
" part " refers to following fact: the light being not all of is diffracted and decouples from waveguide, so that a part of parallel coherent beam
(being actually major part) continues on slab guide propagation.Term " collimated light beam " clearly includes some deviations, according to
These deviations, light are propagated in the waveguide in a manner of being converging or diverging with.The degree of those deviations is by the signal strength detected
Limitation so that contain allows to provide the combination between characterization binding site and target sample at the second focal position in parallel
The deviation of the signal of affinity.Due to the invertibity of the optical path of coherent light, the role of input coupling line and output coupling line is usual
It can exchange, obtain the similar functions of embodiment of the present invention.Binding site can be arranged in more than one a plurality of line
On.Binding site represents the optimal situation that all binding sites are all accurately arranged on ideal line along the arrangement of line.Knot
The optimum layout for closing position is associated with the peak signal at the second focal position, but in fact, the arrangement of binding site will
Deviate the optimum layout to a certain extent, and the decoupling part for the parallel coherent beam for converging to the second focal position is still deposited
?.Multiple input coupling lines and multiple curved output coupling lines are with them in xj、yjPosition on coordinate is carried out by following equation
The mode that geometry limits is arranged on the outer surface of slab guide
Wherein
λ is the vacuum wavelength for propagating light,
N is the effective refractive index of the bootmode in slab guide；N depend on slab guide thickness and refractive index,
The polarization of the refractive index of substrate, the refractive index of medium on the outer surface of slab guide and bootmode,
nsIt is the refractive index of substrate,
F is the distance between focal position and the outer surface of slab guide (focal length),
A0It is to be chosen as close to nsThe integer of f/ λ, and
J is the operation integer for indicating the index of corresponding line.
Selected integer A0Negative x value assignment at line center is negative j value, the positive x value assignment at the center of line is positive j
Value.Or, in other words, integer A0Define the x of the positioning of the line for the outer surface in slab guide, the original of y coordinate system
Point, selected A0Value distribution check bit is set to x=0, y=0, z=-f.
First focal position and the second focal position have approximate 0.5 μm of diameter in a preferable example and are arranged in
At 10-200 μm of distance.
According on one side, multiple input coupling lines are arranged at the first surface portion of the outer surface of slab guide, multiple
Curved output coupling line is arranged at the second surface portion of the outer surface of slab guide.First surface portion includes gutter,
There is no line in the gutter, second surface portion includes another gutter, does not have line in another gutter.Gutter is formed as
2 rank Bragg reflections (the interference maximum value of the coherent light of diffraction at the corresponding multiple lines occurred in slab guide) is avoided,
Or similar optical effect, these may damage the bulk strength of detection signal.Preferably, first surface portion and the second table
Face is all with 25-300 μm of diameter.
First surface portion and second surface portion are arranged in the appearance of slab guide with being spatially separated according to another aspect,
Face.The arrangement that is spatially separated allows at every line of multiple curved output coupling lines the parallel coherent beam of diffraction gradually
Die the largest portion of field (by the wired input coupling of institute of multiple input coupling lines).
According to optional aspect, first surface portion and second surface portion are arranged in the outer surface of slab guide, so as to
The mode that the gutter and another gutter form common gutter is at least partly overlapped.Least partially overlapped
In arrangement, the Minimum Area of the outer surface of slab guide is covered by the first surface portion and second surface portion.Overlay area
Reducing size allows to arrange greater number of this first surface portion and second surface portion in the outer surface of slab guide.
First surface portion and second surface portion are of the same size according to another aspect,.
According to optional aspect, being arranged in the other multiple diffracted rays at least one of output coupling portion further comprises
Multiple straight lines.Straight line the distance between extends parallel to each other and makes adjacent straight line constant, and straight line cloth as follows
Be set to and be at an angle of β relative to the direction of propagation of parallel coherent beam: a part of parallel coherent beam is relative to straight line
Diffraction under angle of diffraction α, so that the diffracted portion of parallel coherent beam hits multiple curved output coupling lines.The combination of attachment
Position is arranged along multiple straight lines or along multiple curved output coupling lines.
The direction of propagation of parallel coherent beam is defined as since multiple input coupling lines and along relevant optical coupling
Extend to the direction in the slab guide for being generally near the direction vertical with multiple input coupling lines.In conjunction with target sample
The coherent light of diffraction hits multiple curved output couplings in second surface portion at the angle of diffraction α relative to straight line at binding site
Zygonema.At angle of diffraction α, the light from multiple straight lines at multiple curved output coupling lines Constructive interaction (that is, in difference
Straight line at diffraction light have predetermined wavelength integral multiple optical path length difference).In view of the folding of scheduled wavelength and substrate
Penetrate rate, the medium of the refractive index of slab guide and the outer surface in slab guide is (for example, the medium in outer surface can be with
Including target sample) refractive index, angle of diffraction α depend on adjacent pre- boning out between constant distance.
According on one side, multiple curved output coupling lines are arranged in the outer surface in the subregion of slab guide,
The part of the parallel coherent beam of diffraction propagates through the subregion at straight line, and other light of parallel coherent beam do not pass
It broadcasts through the subregion.This allows to detect the light at the second focal position in the case where background signal is reduced, because of the second focus
Position is positioned perpendicularly to the region of the outer surface of slab guide, and other " non-diffraction " light of parallel coherent beam are not propagated logical
Cross the region.
Surface covering is arranged on the outer surface of slab guide according to another aspect,.The surface covering has in porous
Portion's structure, the target sample which allows to be applied on coating are diffused through wherein and are reached and slab guide
The binding site of outer surface attachment.Valuably, not only target sample can diffuse through the cellular internal structure of coating and reach
The outer surface of slab guide, target sample can be equally applied in the mixture including other compounds.
In another aspect, the present invention relates to the method for detecting binding affinity, this method comprises the following steps:
Device as described herein is provided,
By the target sample of the binding affinity between binding site to be detected and target sample along at least one is another
Outer multiple diffracted rays are applied in the output coupling portion for the slab guide for being disposed with binding site,
Generate diverging coherent beam: as follows at scheduled first focal position to hit the more of slab guide
A input coupling line, so that the coherent beam of diverging is coupled to the mode in slab guide, to be coupled to the phase of slab guide
Dry light beam is propagated as parallel coherent beam along slab guide and the evanescent field of parallel coherent beam is along its outer surface
The mode of propagation, wherein the part of coherent light by slab guide output coupling portion multiple curved output coupling line diffraction and
So that decoupled it from slab guide in a manner of the decoupling Part Convergence to the second predetermined focal position of coherent light, and
It will detect at second scheduled focal position as the binding affinity between characterization binding site and target sample
Signal coherent light decoupling part.
According to the aspect of this method, with predetermined size and be arranged to include the second predetermined focal position detection zone
The decoupling part of the parallel coherent beam of middle detection, to determine the region in detection zone, wherein predetermined wavelength is relevant
The decoupling part of light has relative maximum intensity.The position of relative maximum intensity is defined as the second predetermined focal position.Relatively
Maximum intensity allows to find the detectable signal in detection zone.The size of detection zone depend on have range 100nm extremely
The manufacturing tolerance of the slab guide of typical thickness in 300nm；The typical manufacturing tolerance of duct thickness is several nanometers.The tolerance
Detection zone corresponding to a few percent for being laterally extended that the order of magnitude is output coupling portion is laterally extended.
According to the another aspect of this method, the coherent beam of diverging with predetermined size and is being arranged to include first predetermined
It is continuously generated at different location in the light beam generating region of focal position.For each coherent beam continuously generated, really
That position with relative maximum intensity for determining the decoupling part of the parallel coherent beam in detection zone, by relative maximum
That position of the highest detection zone of intensity is defined as the second predetermined focal position, and by the generation in light beam generating region
That position of corresponding light beam is defined as the first predetermined focal position.Valuably, relative maximum intensity highest first is defined
Predetermined focal position allows to find the absolute maximum intensity of the best detectable signal at as the second predetermined focal position.This has
Advantage, because different slab guides usually has different thickness, such as in manufacturing tolerance, this be will lead to for every
The position of the first and second predetermined focal positions is different for a equipment.Two scheduled focuses can be found in this manner
The accurate location of position.The size of light beam generating region and the size of detection zone depend on the magnitude of manufacturing tolerance.
In the following, being illustrated to two preferred alternative embodiments according to the method for the present invention.Two embodiments are related to
Binding affinity is detected by using the first and second embodiments for the device for showing manufacturing tolerance respectively.
In first optinal plan of this method, light beam generating region is the appearance that slab guide is parallel in the first plane
The region in face.Detection zone is that the biography of parallel coherent beam is parallel in the second plane of the outer surface for being parallel to slab guide
Broadcast the straight line of direction extension.This allows to detect binding affinity by using device according to first embodiment.It below will ginseng
Fig. 7 is examined working principle and its advantage to be described in detail, to avoid unnecessary repetition herein.
In second optinal plan of this method, light beam generating region is the first of the outer surface for being parallel to slab guide
Region in plane.Detection zone is the region in the second plane of the outer surface for being parallel to slab guide.This allows defeated
It is parallel to also comprise detection at the second predetermined focal position of the device according to this second embodiment of multiple straight lines for coupling part out
Coherent beam decoupling part.Working principle and its advantage will be illustrated below with reference to Fig. 8, to avoid herein
The repetition wanted.
Detailed description of the invention
By the description of the following embodiment of the present invention to reference attached drawing, it is of the invention further beneficial to aspect become it is aobvious and
It is clear to, in the accompanying drawings:
Fig. 1 shows the perspective view of the device of first embodiment according to the present invention, first surface portion and second surface portion
It is arranged in the outer surface of slab guide with being spatially separating；
Fig. 2 shows the perspective view of the device of second embodiment according to the present invention, first surface portion and second surface portion
The outer surface of slab guide is arranged in least partially overlapped mode；
Fig. 3 shows the perspective view of the device of Fig. 2, and it is approximately that first surface portion is Chong Die with second surface portion that substrate, which has,
Size；
Fig. 4 shows the perspective view of the device of Fig. 3, has surface covering；
Fig. 5 shows the perspective view of the device of third embodiment according to the present invention, and output coupling portion further comprises more
Straight line；
Fig. 6 is shown using the first embodiment for detecting the system of the device of binding affinity；
Fig. 7 shows the device of Fig. 1, and the first different focal positions is arranged in light beam generating region, and different
Second focal position is arranged in the detection area, to form straight line in the plane for the outer surface for being parallel to slab guide；
Fig. 8 shows the device of Fig. 5, and the first different focal positions is arranged in light beam generating region, and different
Second focal position is arranged in the detection area, forms area to be formed in the plane for the outer surface for being parallel to slab guide
Domain；And
Fig. 9 shows the system of Fig. 6, including first partial light beam stop part and the second local light beam part light beam backstop
Part.
Specific embodiment
The first embodiment of the apparatus according to the invention 1 is shown by solid in Fig. 1.Slab guide 2 is arranged in
The upper surface of substrate 22 and on it face include outer surface 21.The outer surface 21 of slab guide includes being arranged in first surface portion 3
In multiple input coupling lines 31 and multiple curved output coupling lines 41 for being arranged in second surface portion 4.Multiple bendings
Output coupling line 41 include binding site 51, some of binding sites 51 are combined with target sample 52.
Multiple input coupling lines 31 are bent and are arranged between adjacent input coupling line 31 (from left to right) have gradually
The distance of increasing.By between adjacent lines curvature and cumulative distance be selected as that allow will be from the diverging of the first focal position 611
Coherent beam 61 is coupled in slab guide, and the first focal position 611 is arranged in the downside of substrate 22 in the example shown
Place.System by describing below with reference to Fig. 6 illustrates the generation of the coherent beam 61 of this diverging.The coherent beam 61 of diverging
(or part thereof) by serving as with a plurality of grid line (for example, the periodicity of groove, elongated protrusion, the refractive index of slab guide
Variation) grating multiple input coupling lines 31 and be coupled in slab guide 2.The coherent beam 61 of diverging is coupled to plane wave
It leads and propagates parallel coherent beam 62 along slab guide 2, a part of parallel coherent beam 62 is along outer surface
21 propagate and are formed about evanescent field (not shown) in the outer surface of slab guide 2 21.
As mentioned before, multiple curved output coupling lines 41 include the outer surface 21 for being attached to slab guide 2
Binding site 51.The binding site 51 of some attachments is combined with the target sample 52 on the outer surface 21 for being applied to slab guide 2.
To from left to right there is decrescence distance between the curvature and adjacent input coupling line 31 of multiple curved output coupling lines 41
The arrangement of adjacent input coupling line be selected as parallel coherent beam 62 allowed to decouple so that the solution of parallel coherent beam 63
Coupling Part Convergence is into the second focal position 631.Second focal position 631 is arranged at the downside of substrate 22.Due to tying
Close the decoupling that the parallel coherent beam 63 of the second focal position 631 is converged in the case that position 51 is combined with target sample 52
Partial Strength Changes, so which provide the signals of the binding affinity between characterization binding site 51 and target sample 52
(intensity).
As shown, first surface portion 3 includes gutter 32, second surface portion 4 includes another gutter 42, wherein each
It has been respectively formed the surface region without any line.Gutter 32 and another gutter 42 are spatially kept completely separate.It will be
Optional arrangement is illustrated below.
Optional arrangement is shown in FIG. 2, gutter 32 and another gutter 42 form common gutter 322.The
One surface element 3 and second surface portion 4 arrange in an overlapping arrangement, plurality of input coupling line 31 and multiple curved output couplings
Line 41 be overlapped so that gutter 32 and another gutter 42 " overlapping " and form common gutter 322.In use, it dissipates
Coherent beam 61 be coupled in slab guide 2 by multiple input coupling lines 31 so that parallel coherent beam 62 is along flat
Surface wave leads 2 propagation, and evanescent field is propagated along its outer surface 21.A part of evanescent field (and therefore described light beam) with along
Diffraction at the binding site (not shown) that the target sample (not shown) that multiple curved output coupling lines 41 are arranged combines.Cause
This, a part of parallel coherent beam 62 so that the output coupling Part Convergence of parallel coherent beam 63 to the second focus
Mode in position 631 is decoupled from slab guide 2.In principle, the coherent light of evanescent field is in the engaging portion in conjunction with target sample
Diffraction at position, so that in the engaging portion in conjunction with the target sample along each arrangement in multiple curved output coupling lines 41
The light of diffraction is constructively interfered at the second focal position 631 at position.First focal position 611 and the second adjacent focus position
Set 631 points of distances for opening 10 μm -20 μm.
Fig. 3 shows device 1, the slab guide 2 that device 1 has substrate 22 and is disposed thereon, and has and first
The diameter corresponding with the size that second surface portion 4 is overlapped of surface element 3.It thus provides compact device 1, device 1 has pole
The outer profile of minor diameter, especially diameter are in the range of 25 μm to 500 μm of m, it is therefore preferable to 300 μm of m.
Fig. 4 shows the device 1 according to another advantageous schedule, and wherein surface covering 7, which is formed in, is arranged on substrate 22
On the outer surface of slab guide 2.In this example, surface covering 7 by light absorption (black) film with nano-pore by being covered
The hydrogel of lid is made.These materials have porous internal structure, the porous internal structure have range 5% to
The predetermined hole of predetermined porosity and range in 10nm to 10 μm in 90% (part of the volume in hole relative to total volume)
Size (average diameter in hole).This allows the target sample (for example, certain types of molecule) applied to diffuse through it and reach
With the binding site of outer surface attachment.
Another embodiment of device 1 is depicted by top view in Fig. 5.In left-hand side, it is disposed with multiple input couplings
Line 31 is disposed with multiple curved output coupling lines 41 in right-hand side.Different from described embodiment before, output coupling
Portion additionally includes multiple straight lines 420, these straight lines 420 are arranged between input coupling line 31 and output coupling line 41.At this
In example, binding site (not shown) is arranged along multiple straight lines 420.Straight line 420 is arranged to the distance between adjacent straight line
It is extended parallel to each other in the case where constant.The coherent beam (not shown) of diverging is coupled to flat by multiple input coupling lines 31
Surface wave is led in 2, so that (coherent beam is shown in dotted line, and the diffracted portion of coherent beam is shown as parallel arrow for coherent beam 62
Head) it is propagated together as collimated light beam along slab guide 2 and evanescent field associated with it.Single line in multiple straight lines 420
It is arranged to be at an angle of β about the direction of propagation of parallel coherent beam 62.With the target sample knot arranged along multiple straight lines 420
The binding site of conjunction makes a part (therefore a part of parallel coherent beam) diffraction of evanescent field, and coherent beam 62
The diffracted portion is propagated along slab guide 2 towards multiple curved output coupling lines 41.The portion of parallel coherent beam 62
Divide the diffraction under relative to the angle of diffraction α of straight line (being equal to β).It strikes on multiple curved output coupling lines 41 and wherein one
The intensity of the diffracted portion of the parallel coherent beam 62 decoupled from slab guide 2 is divided to provide the letter of characterization binding affinity
Number, and described in first embodiment.
Fig. 6 shows the system 10 for detecting binding affinity.System 10 includes laser light source 11,11 energy of laser light source
It is enough that the coherent beam 61 of diverging is provided at the first focal position 611 of device 1 (as described above).Laser light source 11 generates relevant
Light beam, condenser lens 12 focus on the coherent beam on the first focal position 611.Light scanning unit 12,17 includes scanning
Instrument 17 and condenser lens 12 and the coherent beam 61 of diverging is generated in light beam generating region (as with reference to illustrated by Fig. 7 and Fig. 8
).The coherent beam 61 of diverging from the first focal position 611, which is coupled in slab guide 2 and produces, converges to second
The decoupling part 63 of diffraction coherent light on focal position 631.System 10 further comprises optical detecting unit, the light detection list
Member, which provides, to be spread out by being arranged in behind diaphragm 14 fluorescence detector 13 (when looking up in the side of optical path) to detect
Penetrate the spatial filter 100 of the intensity of the converging beam of the decoupling part 63 of coherent light.Fluorescence detector 13 is perpendicular to optical axis 18
Extend.Diaphragm 14 is arranged on movable positioning supporting part 15.The extension that diaphragm 14 is parallel to fluorescence detector 13 can be moved into
The masked position of any light other than the light from the second focal position 631, so that only from the second focal position
631 light is just struck on fluorescence detector 13 by the opening 141 in diaphragm 14.It is arranged in movable positioning supporting part 15
On diaphragm 14 allow be arranged in the plane for the outer surface for being parallel to slab guide it is opposite (that is, in the detection area)
The decoupling part 63 of detection of diffracted coherent beam at different location at the different positioning of multiple curved output coupling lines 41.
In other words, using the device as described above 1 of detection binding affinity (that is, according to appointing in device claim
One) system 10 includes
Light source 11 and light scanning unit 12,17 can be according to the of the devices 1 of any one of device claim
The light beam of diverging is generated at one focal position 611, to allow to provide the diffraction coherent light converged in the second focal position 631
Part 63 is decoupled, and
Optical detection unit 13,14,16,20 is able to detect the intensity of the convergence beam of the decoupling part 63 of diffraction coherent light.
Optical detection unit 13,14,16,20 includes being arranged in the subsequent fluorescence detector 13 of diaphragm 14 with opening 141.Optics inspection
Surveying unit 13,14,16,20 further comprises beam splitter 16, the second condenser lens 20 and the movable positioning support for diaphragm 14
Part 15.The convergence beam (decoupling part 63) of diffraction coherent light is focused saturating by condenser lens 12, scanner 17, beam splitter 16 and second
Mirror 20 emits and strikes on diaphragm 14.It is arranged on movable positioning supporting part 15 by mobile in the plane perpendicular to optical axis
Diaphragm 14, the opening 141 in diaphragm 14 can be located in the second focus of the decoupling part 63 (convergence beam) of diffraction coherent light
At the optical conjugate position of position 631.At the position of diaphragm 14, the decoupling part 63 of diffraction coherent light (convergence beam) is passed through
It opening 141 in diaphragm 14 and strikes on detector 13, wherein measuring the solution of diffraction coherent light by fluorescence detector 13
The intensity of coupling part 63.
Valuably, system 10 further comprises above-mentioned device 1.
Fig. 7 and Fig. 8 are illustrated together below, because they are directed to generate diverging in light beam generating region 612
Coherent beam 61 and in detection zone 632 detection converge to the second focal position 631 diffraction coherent beam decoupling
The same technical solution of part 63.Even if allowing in this way using with by structural deviation (example caused by the manufacture of the device 1
Such as, variation of the thickness of slab guide within the scope of typical manufacturing tolerance) device 1 can also detect the second focal position
Signal at 631.In other words, allow absolutely not accurately known in the wherein position of the first focal position and the second focal position
Binding affinity is detected in device 1.
It, will (output coupling portion only includes multiple curved output couplings about device 1 according to first embodiment with reference to Fig. 7
Zygonema) come describe in the detection zone 632 of the second focal position 631 detect maximum intensity signal method.Device 1 has flat
Surface wave leads 2, which has the thickness generated by the known manufacturing tolerance in several nanometer ranges.In light beam
The coherent beam 61 of diverging is continuously generated at the different location of generating region 612.Light beam generating region 612 is arranged on for example
Border circular areas at the lower surface (the first plane as the outer surface for being parallel to waveguide) of substrate 22, and there is the system of depending on
Make the size of tolerance.For each coherent beam 61 continuously generated, determine the decoupling part 63 of diffraction coherent light relatively most
The position occurred in big intensity detection region 632.Relative maximum intensity is determined, so as to along straight line 632 (as detection zone)
Detect the decoupling part 63 of (with scanning mode) diffraction coherent light 63.This allows about generating in light beam generating region 612
The coherent beam 61 of each diverging determines that the relative maximum intensity of the decoupling part 63 of diffraction coherent beam appears in straight line 632
That position.Then, the second focal position 631 is defined as that position for highest relative maximum intensity occur.Finally,
By that position for leading to highest relative maximum intensity at the second focal position 631 in the light beam generating region 612 for generating light beam
It sets and is defined as the first focal position 611.
Construction shown in Fig. 7 is examined only along straight line 632 (rather than in the detection zone formed by region)
Survey is possible, because the little deviation of the direction of propagation of coherent beam 62 can generate at the second focal position 631 in the waveguide
Identical absolute maximum intensity.In principle, this method can be implemented in turn, that is, along the continuously detection of diffracted phase of straight line 632
The decoupling part 63 of dry light 63, for continuously detecting each of position detection position, in entire light beam generating region 6
All positions at generate diverging coherent beam 61 with allow detect maximum intensity at the second focal position 631.
In fig. 8, about device 1 according to the third embodiment, (output coupling portion includes multiple curved output coupling lines
The method that the signal of maximum intensity is detected in the region of the second focal position 631 is described with multiple straight lines, Fig. 5).It overlooks
The construction is shown in figure more preferably to illustrate to provide.As described above, 3rd embodiment the difference is that, in addition want
Meet the diffraction conditions (Bragg condition) at multiple straight lines 42.The additional requirement implys that, single first burnt of only one
Point position 611 and corresponding the second single focal position 631 of only one meet coherent light maximum be coupled in slab guide,
Maximum coupling and the maximum condition being coupled out from slab guide in slab guide.Therefore, at the second focal position 631
Detection will not being straight line (be different from Fig. 7) but carried out in the detection zone 633 in a region.The coherent beam of diverging
61 continuously result from the different location in light beam generating region 612.Light beam generating region 612 is arranged on for example to be formed thereon
There is the border circular areas at the lower surface of the substrate of slab guide.For each coherent beam (not shown) continuously generated, determine
That position with relative maximum intensity of the decoupling part of diffraction coherent light (not shown) in detection zone 632.Relatively most
Big intensity is the maximum intensity by the decoupling part of diffraction coherent light in detection border circular areas 633 (as detection zone) come really
Fixed.This allows the coherent beam 61 of the diverging for each generation to determine that the decoupling part of diffraction coherent light in border circular areas has
There is that position of relative maximum intensity.Second focal position 631 is limited at that with highest relative maximum intensity
At position (in this embodiment, only one position in detection zone).Finally, generate beam light beam generating region 612 in
That position that second focal position generates highest relative maximum intensity is defined as the first focal position 611.
Fig. 9 shows system 10, and the principle of system 10 is illustrated above in conjunction with Fig. 6.However, from structure
On say, system shown in Fig. 9 the difference is that comprising first partial light beam stop part 19 and the second local light beam stop part
191。
In the use process of system 10, use device 1.In this example, device 1, which has, is arranged in local first surface
Input coupling line 31 in portion 311 and the curved output coupling line 41 being arranged in local second surface portion 411.Part the
One surface element 311 and local second surface portion 411 are not overlapped, so that multiple input coupling lines 31 and multiple curved output couplings
Zygonema is arranged to be spatially separated.Target sample (not shown) is applied in this example along curved output coupling line 41
It arranges on the binding site of (but usually can equally be arranged at multiple input coupling lines 31).
In device use process, it is similar to Fig. 6, the diverging that input coupling line 31 will generate at the first focal position
Coherent beam 61 is coupled in slab guide and (does not have in current view separately shown).The coherent beam being coupled in waveguide is made
It is propagated together with its evanescent field for light 62.With the decoupling Part Convergence of diffraction coherent light 63 to the second focal position to be detected
Mode is by multiple curved output coupling lines 41 by a part of evanescent field (and one of the light beam for therefore propagating through waveguide
Part) it is diffracted to the signal for characterizing the binding affinity between binding site and target sample.
Valuably, first partial light beam stop part 19 limits the coherent light that (that is, passing through masking) is generated by laser light source 11
Beam.Therefore, the coherent beam 61 of restricted diverging only irradiates the first partial surface element including multiple input coupling lines 31
311.In other words, the first light beam stop part 19 limits coherent light as follows: only input coupling line 31 is illuminated, not light court
It is propagated to the second local surface element 411 for being disposed with curved output coupling line 41.This is for by preventing from detecting coherent light
Reflective portion come particularly advantageous for bias light of decaying.
Second light beam stop part 191 with shelter in addition to the diffraction at curved output coupling line 41 and then propagate through every
Film 14 and the mode for reaching the light except the light of fluorescence detector 13 is arranged along the propagation path of the decoupling part 63 of coherent light.
Claims (12)
1. a kind of device (1) for detecting binding affinity, described device (1) includes the plane wave being arranged on substrate (22)
It leads (2), the slab guide (2) has outer surface (21) and multiple input coupling lines (31), the multiple input coupling line
For coherent beam to be coupled in the slab guide (2), so that coherent beam (62) parallel in operation is along described
Slab guide (2) is propagated and evanescent field is propagated along its outer surface (21), which is characterized in that the multiple input coupling line
(31) it is curved and is arranged to when being watched on the direction of propagation of the parallel coherent beam (62) along the slab guide
There is cumulative distance, the arrangement of the multiple input coupling line and adjacent input coupling between adjacent input coupling line (31)
The distance between zygonema makes, and in operation, from scheduled first focal position (611) and hits the multiple input coupling
The coherent beam (61) of the diverging of the predetermined wavelength of line is coupled in the slab guide (2), so that parallel coherent beam
(62) it is propagated along the slab guide (2), wherein capableing of multiple binding sites (51) of combining target sample along being arranged in
At least one of multiple diffracted rays in the output coupling portion of the slab guide (2) is attached on the outer surface (21), institute
At least one for stating multiple diffracted rays includes multiple curved output coupling lines (41), the multiple curved output coupling line
(41) be arranged to when hitting the side of propagation of parallel coherent beam (62) above it and looking up adjacent curved
There is distance decrescence between bent output coupling line, the predetermined wavelength of the curved output coupling line is hit so as to diffraction
Parallel coherent beam (62) a part so that its from the slab guide (2) decouple so that the coherent light of predetermined wavelength
Decoupling part (63) converge to scheduled second focal position (631), thus at second focal position (631) provide
The signal of the binding affinity between the binding site (51) and the target sample (52) is characterized,
Wherein, the multiple input coupling line (31) is arranged in the first table of the outer surface (21) of the slab guide (2)
At facial (3), and the multiple curved output coupling line (41) is arranged in the outer surface of the slab guide (2)
(21) at second surface portion (4), the first surface portion (3) includes gutter (32), is not had in the gutter (32)
Line, and the second surface portion (4) includes another gutter (42), does not have line in another gutter (42).
2. the apparatus according to claim 1 (1), wherein the first surface portion (3) and the second surface portion (4) are empty
Between be discretely arranged at the outer surface (21) of the slab guide (2).
3. the apparatus according to claim 1 (1), wherein the first surface portion (3) and the second surface portion (4) are extremely
Small part is overlappingly arranged at the outer surface (21) of the slab guide (2), so that the gutter (32) and described
Another gutter (42) forms common gutter (322).
4. the apparatus according to claim 1 (1), wherein first surface portion (3) and second surface portion (4) are having the same
Size.
5. the apparatus according to claim 1 (1), wherein the multiple diffracted ray being arranged in the output coupling portion
At least one further comprise multiple straight lines (420), the straight line extends parallel to each other, between adjacent straight line have perseverance
Fixed distance, and the straight line is arranged to be at an angle of (β) relative to the direction of propagation of the parallel coherent beam (62), makes
Parallel coherent beam (62) a part relative to the straight line at the angle of diffraction (α) under diffraction, so that parallel is relevant
The diffracted portion of light beam (62) hits multiple curved output coupling lines (41), and the binding site (51) wherein adhered to along
The multiple straight line (420) is arranged along the multiple curved output coupling line (41).
6. device (1) according to claim 5, wherein the multiple curved output coupling line (41) is arranged in described
At outer surface (21) in the subregion (23) of slab guide (2), the parallel coherent beam of diffraction at the straight line (420)
(62) part propagates through the subregion (23), and other light of parallel coherent beam (62) are not propagate through described point
Area (23).
7. device (1) according to any one of the preceding claims, wherein surface covering (7) is arranged in the plane
On the outer surface (21) of waveguide (2), the surface covering (7) has cellular internal structure, described to allow to be applied to
Target sample (52) on coating (7) diffuses through it and reaches the outer surface (21) for being attached to the slab guide (2)
On the binding site (51).
8. a kind of method for detecting binding affinity, the described method comprises the following steps:
Device (1) according to any one of the preceding claims is provided,
To be used for the target sample (52) of the binding affinity between binding site to be detected (51) and target sample (52) along
At least one of multiple diffracted rays is applied to the output coupling portion for being disposed with the slab guide (2) of the binding site (51)
On,
The coherent beam (61) of diverging is generated, at scheduled first focal position (611) to hit the slab guide (2)
The multiple input coupling line (31), by diverging coherent beam (61) be coupled in the slab guide (2), thus coupling
Coherent beam in slab guide is closed to propagate as parallel coherent beam (62) along the slab guide (2) and parallel
The evanescent field of coherent beam (62) is propagated along its outer surface (21), wherein a part of parallel coherent beam (62) is by described
Multiple curved output coupling line (41) diffraction in the output coupling portion of slab guide (2), so that its described slab guide (2) solution
Coupling, so that the decoupling part (63) of the coherent light converges to the second predetermined focal position (631),
Detection is as the characterization binding site (51) and the target sample at second predetermined focal position (631)
(52) the decoupling part (63) of the coherent light of the signal of the binding affinity between, and
By the intensity for being located at coherent light at scheduled second focal position carry out detection and with only applied by not having
The known strength of the coherent light of the binding site diffraction of target sample is compared.
9. according to the method described in claim 8, wherein, with scheduled size and it is being arranged to include the described second pre- fixed-focus
The decoupling part (63) of detection coherent light in the detection zone (632) of point position (631), with the determination detection zone (632)
In the decoupling part (63) of coherent light of predetermined wavelength there is that position of relative maximum intensity, and it is relative maximum is strong
The position restriction of degree is the second predetermined focal position (631).
10. according to the method described in claim 9, wherein, with scheduled size and it is being arranged to include first focusing in advance
The coherent beam (61) that diverging is continuously generated at different location in the light beam generating region (612) of position (611), wherein right
In the coherent beam (61) of each diverging continuously generated, the decoupling part of the coherent light in detection zone (632,633) is determined
(63) with relative maximum intensity that position, with will test relative maximum intensity in region (632,633) it is highest that
Position restriction is the second predetermined focal position (631), and by the corresponding light beam of generation in the light beam generating region (612)
That position restriction is the first predetermined focal position (611).
11. according to the method described in claim 10, wherein, the light beam generating region (612) is parallel to the plane wave
Lead the region in the first plane of the outer surface (21) of (2), and wherein, the detection zone (632) be be parallel to it is described
It is parallel to the direction of propagation of parallel coherent beam (62) in second plane of the outer surface (21) of slab guide (2) and extends
Straight line.
12. according to the method described in claim 10, wherein, the light beam generating region (612) is parallel to the plane wave
The region in the first plane of the outer surface (21) of (2) is led, and wherein the detection zone (633) is parallel to the plane
Region in second plane of the outer surface (21) of waveguide (2).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP13176362.5A EP2824446A1 (en) | 2013-07-12 | 2013-07-12 | Device for use in the detection of binding affinities |
| EP13176362.5 | 2013-07-12 | ||
| PCT/EP2014/064884 WO2015004264A1 (en) | 2013-07-12 | 2014-07-11 | Device for use in the detection of binding affinities |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105378463A CN105378463A (en) | 2016-03-02 |
| CN105378463B true CN105378463B (en) | 2019-07-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201480039853.4A Active CN105378463B (en) | 2013-07-12 | 2014-07-11 | For detecting the device of binding affinity |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US10060917B2 (en) |
| EP (2) | EP2824446A1 (en) |
| JP (1) | JP6358482B2 (en) |
| KR (1) | KR102254595B1 (en) |
| CN (1) | CN105378463B (en) |
| BR (1) | BR112015028926B1 (en) |
| CA (1) | CA2917979C (en) |
| HK (1) | HK1221770A1 (en) |
| MX (1) | MX2016000288A (en) |
| RU (1) | RU2655037C2 (en) |
| WO (1) | WO2015004264A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2618130A1 (en) * | 2012-01-17 | 2013-07-24 | F. Hoffmann-La Roche AG | Device for use in the detection of binding affinities |
| DE102017211910A1 (en) | 2017-07-12 | 2019-01-17 | Dr. Johannes Heidenhain Gmbh | Diffractive biosensor |
| WO2019166562A1 (en) | 2018-03-01 | 2019-09-06 | F. Hoffmann-La Roche Ag | Device for use in the detection of binding affinities |
| RU2737056C1 (en) | 2018-03-29 | 2020-11-24 | Иллюмина, Инк. | Lighting for fluorescent imaging using objective lens |
| CN112424584A (en) | 2018-07-18 | 2021-02-26 | 约翰内斯·海德汉博士有限公司 | Diffraction biosensor |
| DE102020212029A1 (en) | 2020-09-24 | 2022-03-24 | Dr. Johannes Heidenhain Gmbh | Device and method for the simultaneous imaging of two object planes |
| DE102020212031A1 (en) | 2020-09-24 | 2022-03-24 | Dr. Johannes Heidenhain Gmbh | Device and method for determining the intensity of light guided in a planar waveguide IWG(x, y) |
| WO2023187078A1 (en) | 2022-03-30 | 2023-10-05 | Miltenyi Biotec B.V. & Co. KG | White light scattering in optical biomolecule interaction analysis |
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- 2013-07-12 EP EP13176362.5A patent/EP2824446A1/en not_active Ceased
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2014
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- 2014-07-11 JP JP2016524836A patent/JP6358482B2/en active Active
- 2014-07-11 BR BR112015028926-6A patent/BR112015028926B1/en active IP Right Grant
- 2014-07-11 RU RU2016104217A patent/RU2655037C2/en active
- 2014-07-11 MX MX2016000288A patent/MX2016000288A/en unknown
- 2014-07-11 CN CN201480039853.4A patent/CN105378463B/en active Active
- 2014-07-11 KR KR1020167003562A patent/KR102254595B1/en active IP Right Grant
- 2014-07-11 US US14/904,039 patent/US10060917B2/en active Active
- 2014-07-11 WO PCT/EP2014/064884 patent/WO2015004264A1/en active Application Filing
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| US5071248A (en) * | 1985-05-29 | 1991-12-10 | Asi Ag | Optical sensor for selective detection of substances and/or for the detection of refractive index changes in gaseous, liquid, solid and porous samples |
| US5081012A (en) * | 1988-03-29 | 1992-01-14 | Applied Research Systems Ars Holding N.V. | Waveguide sensor with input and reflecting gratings and its use in immunoassay |
| EP1085315A1 (en) * | 1999-09-15 | 2001-03-21 | CSEM Centre Suisse d'Electronique et de Microtechnique SA | Integrated-optical sensor |
| CN101368912A (en) * | 2004-07-30 | 2009-02-18 | 株式会社东芝 | Optical biologic sensor |
Also Published As
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|---|---|
| WO2015004264A1 (en) | 2015-01-15 |
| MX2016000288A (en) | 2016-04-25 |
| JP2016524163A (en) | 2016-08-12 |
| EP3019856B1 (en) | 2021-11-03 |
| CA2917979C (en) | 2021-11-02 |
| KR102254595B1 (en) | 2021-05-24 |
| KR20160029852A (en) | 2016-03-15 |
| RU2016104217A (en) | 2017-08-16 |
| BR112015028926B1 (en) | 2020-10-06 |
| BR112015028926A2 (en) | 2017-07-25 |
| HK1221770A1 (en) | 2017-06-09 |
| EP3019856A1 (en) | 2016-05-18 |
| JP6358482B2 (en) | 2018-07-18 |
| US20160161477A1 (en) | 2016-06-09 |
| EP2824446A1 (en) | 2015-01-14 |
| RU2016104217A3 (en) | 2018-03-22 |
| CN105378463A (en) | 2016-03-02 |
| RU2655037C2 (en) | 2018-05-23 |
| US10060917B2 (en) | 2018-08-28 |
| CA2917979A1 (en) | 2015-01-15 |
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